2.1. THE COMPLEMENT SYSTEM
The complement system is a group of proteins that constitutes about 10 percent of the globulins in the normal serum of humans (Hood, L. E. et al. 1984, Immunology, 2d Edition, The Benjamin/Cummings Publishing Co., Menlo Park, Calif., p. 339). Complement (C) plays an important role in the mediation of immune and allergic reactions (Rapp, H. J. and Borsos, T., 1970, Molecular Basis of Complement Action, Appleton-Century-Crofts (Meredith), New York). The activation of C components leads to the generation of a group of factors, including chemotactic peptides that mediate the inflammation associated with complement-dependent diseases. The sequential activation of the complement cascade may occur via the classical pathway involving antigen-antibody complexes, or by an alternative pathway which involves the recognition of certain cell wall polysaccharides. The activities mediated by activated complement proteins include lysis of target cells, chemotaxis, opsonization, stimulation of vascular and other smooth muscle cells, degranulation of mast cells, increased permeability of small blood vessels, directed migration of leukocytes, and activation of B lymphocytes, macrophages and neutrophils (Eisen, H. N., 1974, Immunology, Harper & Row, Publishers, Inc., Hagerstown, Md., p. 512).
During proteolytic cascade steps, biologically active peptide fragments, the anaphylatoxins C3a, C4a, and C5a (See WHO Scientific Group, WHO Tech. Rep. Ser. 1977, 606, 5 and references cited therein), are released from the third (C3), fourth (C4), and fifth (C5) native complement components (Hugli, T. E. CRC Crit. Rev. Immunol. 1981, 1, 321; Bult, H. and Herman, A. G. Agents Actions 1983, 13, 405). The C5a fragment, a cationic peptide derived from the first 74 amino acids of the amino-terminus of the C5 alpha subunit (Tack, B. F. et al. Biochemistry 1979, 18, 1490), is of particular pathological relevance. Regulation of C5a activity is by the endogenous plasma enzyme carboxypeptidase N (E.C. 3.4.12.7), which rapidly removes the carboxy-terminal arginine from C5a, producing the less potent but still active C5a des Arg. Reported effects of C3a and C5a upon specific immune responses are listed in Table I.
TABLE I ______________________________________ EFFECTS OF COMPLEMENT COMPONENTS C3a AND C5a ON SPECIFIC IMMUNE RESPONSES Immune Response C3a C5a/C5a des Arg ______________________________________ Specific antibody production in response to: Sheep red blood cells Suppression Enhancement Polyclonal antibody production in response to: Fc antibody fragment Suppression Enhancement T cell proliferation in response to: Tetanous toxoid Suppression Enhancement Mixed lymphocyte No effect Enhancement T cell-mediated cytotoxicity Suppression Enhancement ______________________________________
Among the wide variety of biological activities exhibited by C5a are contraction of smooth muscle (Wissler, J. H. Eur. J. Immunol. 1972, 2, 73), degranulation of mast cells (Johnson, A. R. et al. Immunol. 1975, 28, 1067), secretion of azurophilic granular enzymes from polymorphonuclear neutrophils (PMN) (Webster, R. O. et al. Immunopharmacol. 1980, 2, 201), and the chemotaxis of PMN (Wissler, J. H. Eur. J. Immunol. 1972, 2, 73; Becker, E. L. Trends Pharmacol. Sci. 1983, 4, 223) (Table II).